Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity and previous treatment history in the OTEMTO studies

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1 Sigh et al. Respiratory Research (2016) 17:73 DOI /s RESEARCH Ope Access Effects of tiotropium + olodaterol versus tiotropium or placebo by COPD disease severity ad previous treatmet history i the OTEMTO studies Dave Sigh 1*, Mia Gaga 2, Olaf Schmidt 3, Leif Bjermer 4, Lars Gröke 5, Floria Voß 5 ad Gary T. Ferguso 6 Abstract Backgroud: As lug fuctio declies rapidly i the early stages of chroic obstructive pulmoary disease (COPD), the effects of brochodilators i patiets with moderate disease ad those who have ot previously received maiteace therapy are of iterest. OTEMTO 1 ad 2 were two replicate, 12-week, Phase III studies ivestigatig the beefit of tiotropium + olodaterol o lug fuctio ad quality of life i patiets with moderate to severe disease. Post hoc aalyses were performed to assess the beefits for patiets accordig to disease severity ad treatmet history. Methods: Four subgroup aalyses were performed: Global iitiative for chroic Obstructive Lug Disease (GOLD) 2/3, GOLD A/B/C/D, treatmet aive/ot treatmet aive ad receivig ihaled corticosteroids (ICS) at baselie/ot receivig ICS at baselie. Primary ed poits were chage i forced expiratory volume i 1 s (FEV 1 ) area uder the curve from 0 to 3 h respose, chage i trough FEV 1 ad St George s Respiratory Questioaire (SGRQ) total score. Trasitio Dyspoea Idex (TDI) focal score was a secodary ed poit, ad SGRQ ad TDI respoder aalyses were further ed poits; all were assessed at 12 weeks. Results: I all subgroups, patiets receivig tiotropium + olodaterol respoded overall tha those receivig tiotropium mootherapy. Improvemets with tiotropium + olodaterol over placebo or tiotropium mootherapy were oted across /3 ad GOLD A/B/C/D; however, improvemets i SGRQ total score were most evidet i the GOLD B subgroup. Moreover, lug-fuctio outcomes were geerally greater i those patiets who had bee receivig previous log-actig brochodilator ad/or ICS maiteace treatmet. Coclusios: These data suggest that tiotropium + olodaterol should be cosidered as a treatmet optio i patiets with moderate COPD who are iitiatig maiteace therapy, as well as those with more severe disease. Trial registratio: CliicalTrials.gov: NCT ad NCT Keywords: COPD, Log-actig brochodilator, Tiotropium, Olodaterol, Severity, Treatmet history * Correspodece: dsigh@meu.org.uk 1 Cetre for Respiratory Medicie ad Allergy, The Medicies Evaluatio Uit, Uiversity Hospital of South Machester Foudatio Trust, Uiversity of Machester, Machester, Southmoor Road, Machester M23 9QZ, UK Full list of author iformatio is available at the ed of the article 2016 The Author(s). Ope Access This article is distributed uder the terms of the Creative Commos Attributio 4.0 Iteratioal Licese ( which permits urestricted use, distributio, ad reproductio i ay medium, provided you give appropriate credit to the origial author(s) ad the source, provide a lik to the Creative Commos licese, ad idicate if chages were made. The Creative Commos Public Domai Dedicatio waiver ( applies to the data made available i this article, uless otherwise stated.

2 Sigh et al. Respiratory Research (2016) 17:73 Page 2 of 13 Backgroud The use of log-actig β 2 -agoists (LABAs) ad logactig muscariic atagoists (LAMAs) is cetral to the pharmacological maagemet of patiets with chroic obstructive pulmoary disease (COPD) [1, 2]. The aim of treatmet is to improve lug fuctio, reduce symptoms ad risk of exacerbatios, ad improve health status [1]. Tiotropium is a established oce-daily LAMA that improves lug fuctio, patiet-reported outcomes such as dyspoea ad quality of life, ad reduces exacerbatios i patiets with COPD [3 9]. Olodaterol is a ovel LABA that provides 24-h brochodilatio ad symptomatic beefits i patiets with COPD [10 13]. The combiatio of tiotropium + olodaterol has bee extesively studied i a large Phase III cliical trial programme that demostrated improvemets i lug fuctio ad patiet-reported outcomes compared to tiotropium mootherapy, with tolerability similar to tiotropium [14 18]. A recet post hoc aalysis of the TONADO studies showed that tiotropium + olodaterol sigificatly improved lug fuctio i Global iitiative for chroic Obstructive Lug Disease (GOLD) severity groups 2, 3 ad 4, compared to mootherapy, irrespective of whether patiets had received prior LAMA or LABA maiteace treatmet [19]. The OTEMTO studies were two replicate, radomised, double-blid, Phase III studies ivestigatig the effects of tiotropium + olodaterol o lug fuctio ad quality of life [16]. Ulike the TONADO trials, OTEMTO icluded a placebo arm as well as tiotropium as a active comparator i order to properly uderstad the effect size of tiotropium + olodaterol o patiet-reported outcomes. Overall, tiotropium + olodaterol was superior to tiotropium at improvig quality of life as measured by the St George s Respiratory Questioaire (SGRQ) ad, importatly, the improvemet versus placebo was >4 uits (the miimum cliically importat differece) [16]. The OTEMTO studies provided the opportuity to study the effectiveess of tiotropium + olodaterol i differet COPD subgroups based o lug fuctio (GOLD 2 or 3), GOLD combied assessmet (A, B, C or D) ad previous treatmet focusig o treatmet-aive patiets (o prior use of LAMAs, LABAs ad/or ihaled corticosteroids [ICS]). We, therefore, performed post hoc aalyses to evaluate the efficacy of tiotropium + olodaterol compared to placebo ad tiotropium mootherapy i subgroups of patiets defied by GOLD category ( 3 adgolda D) ad by previous treatmet history (treatmet aive ad baselie ICS use) after 12 weeks of treatmet. The aim of this aalysis was to uderstad if the beefits of tiotropium + olodaterol vary accordig to GOLD categorisatio or previous treatmet. Methods Study desig As preseted elsewhere [16], OTEMTO 1 ( ; NCT ) ad 2 ( ; NCT ) were two replicate, double-blid, placebo-cotrolled studies. Patiets were radomised to oe of four treatmet arms to receive oce-daily tiotropium + olodaterol 2.5/5 μg, tiotropium + olodaterol 5/5 μg, tiotropium 5 μg or placebo, all delivered via the Respimat ihaler. Patiets Patiets were icluded if they were aged 40 years with moderate or severe COPD ( 3; postbrochodilator forced expiratory volume i 1 s [FEV 1 ] <80 % ad 30 % of predicted ormal), FEV 1 /forced vital capacity <70 % predicted ad a smokig history of >10 pack-years. Exclusio criteria icluded sigificat disease other tha COPD, a history of asthma, COPD exacerbatio or symptoms of lower respiratory tract ifectio withi the previous 3 moths. Patiets cotiued their ICS therapy if they were o a stable dose for 6 weeks prior to screeig but were ot permitted to take LAMAs or LABAs other tha study medicatio. Short-actig muscariic atagoists were permitted oly durig the screeig period ad opelabel salbutamol was provided as rescue medicatio for use throughout the study. The studies were coducted i accordace with the Declaratio of Helsiki, Iteratioal Coferece o Harmoisatio Harmoised Tripartite Guidelie for Good Cliical Practice ad local regulatios. Siged, iformed coset was obtaied from all patiets. The studies were approved by the relevat Istitutioal Review Board/Idepedet Ethics Committees ad competet authorities; full details are icluded i Additioal file 1. Outcomes There were three primary ed poits i the OTEMTO studies, all at 12 weeks: SGRQ total score, chage from baselie i trough FEV 1 ad chage from baselie i FEV 1 area uder the curve from 0 to 3 h (AUC 0 3 ). Mahler Trasitio Dyspoea Idex (TDI) focal score was a secodary ed poit; respoder aalyses for SGRQ ad TDI focal scores were further ed poits. Assessmets As described i the primary mauscript [16], pulmoary fuctio tests were performed at 1 h pre-dose, 10 mi predose,5,15ad30mipost-dosead1,2ad3hpostdose at baselie ad week 12, ad at 10 mi pre-dose oly after 2 ad 6 weeks of treatmet. The fial trough FEV 1 measuremet was take the day after the week 12 visit (at 23 h ad 23 h 50 mi post-dose). SGRQ was completed i the cliic at baselie ad weeks 6 ad 12. At weeks 6 ad

3 Sigh et al. Respiratory Research (2016) 17:73 Page 3 of 13 12, traied cliic staff coducted the TDI iterview, which asks patiets about breathlessess compared to baselie. Subgroup aalysis For all of the post hoc aalyses preseted here, data from OTEMTO 1 ad 2 were combied to icrease the robustess of the aalyses. As tiotropium + olodaterol 5/5 μg is theliceseddose,weareolypresetigtheresultsof these subgroup aalyses for the tiotropium + olodaterol 5/5 μg, tiotropium 5 μg ad placebo groups. Four subgroup aalyses were performed: or 3, GOLD A D (based o the modified Medical Research Coucil dyspoea scale), maiteace treatmet aive (o prior use of LAMAs, LABAs ad/or ICS) ad baselie use of ICS. Results are preseted for the three primary ed poits (FEV 1 AUC 0 3 respose, trough FEV 1 respose ad SGRQ total score), the SGRQ respoder aalysis, TDI focal score ad TDI focal score respoder aalysis. For the SGRQ respoder aalysis, patiets were classed as respoders if their SGRQ total score improved from baselie to week 12 by 4 uits. Odds ratios were calculated betwee groups usig a logistical regressio icludig the fixed categorical effect of treatmet. A restricted maximum likelihood-based mixed effects model repeated measures approach was used for the aalysis of cotiuous ed poits, icludig the fixed categorical effects of treatmet, test day ad treatmet-by-test-day iteractio, as well as the cotiuous fixed covariates of baselie ad baselie-by-test-day iteractio. The TDI respoder aalysis was based o the TDI focal score; patiets were classed as respoders if they had a value that was 1.0 uit. As these aalyses are post hoc ad performed withi subgroups with potetially small sample sizes, they are ot powered for statistical comparisos withi subgroups; therefore, results are preseted as forest plots of treatmet differeces with correspodig 95 % cofidece itervals (CIs). Differeces i treatmet effects betwee subgroups are discussed ad emphasis is ot put o statistical sigificace withi subgroups aloe (assessed based o the 95 % CI). No adjustmet for multiple comparisos has bee performed. Results Patiet dispositio ad baselie characteristics I OTEMTO 1 ad 2, a total of 1623 patiets were radomised, with 1621 receivig treatmet ad 1525 completig the study (Fig. 1). Patiet demographics ad 2161 screeed 538 ot radomised 1623 radomised 1 patiet ot treated a Treated set = (5.9 %) discotiued from trial medicatio: 46 adverse evets 21 worseig of disease uder study 4 worseig of other pre-existig disease 21 other adverse evet 17 lack of efficacy 10 o-compliat 3 lost to follow-up 15 coset withdraw 5 other reaso Completed 1525 (94.1 %) Fig. 1 Patiet dispositio i OTEMTO 1 ad 2 (combied data). a 1623 patiets were radomised; 1 patiet was etered twice but couted oly oce i the treated set

4 Sigh et al. Respiratory Research (2016) 17:73 Page 4 of 13 baselie characteristics by subgroup ad overall populatio are show i Table 1. Overall baselie characteristics such as age ad sex were similar across subgroups. As expected, mea FEV 1 values ad baselie pulmoary medicatios also differed betwee subgroups. Patiets who were already receivig maiteace therapy teded to be ex-smokers ad to have worse lug fuctio compared to those who were treatmet aive. Efficacy ad 3 subgroups Trough FEV 1 resposes ad SGRQ total scores improved with tiotropium + olodaterol i both ad 3 subgroups after 12 weeks of treatmet compared to baselie (Figs. 2 ad 3). I the subgroup, the adjusted mea (stadard error) SGRQ total score chage from baselie at week 12 was 4.7 (0.6) i the tiotropium + olodaterol 5/5 μg arm, 2.2 (0.6) i the tiotropium 5 μgarmad 0.7 (0.6) i the placebo arm. I the subgroup, the adjusted mea (stadard error) SGRQ total score chage from baselie at week 12 was 5.6 (0.8) i the tiotropium + olodaterol 5/5 μg arm, 4.2 (0.9) i the tiotropium 5 μg arm ad 0.5 (0.9) i the placebo arm. Similar improvemets were also see i the absolute SGRQ score (Additioal file 1: Table S1). Improvemets after 12 weeks compared to baselie were also observed for tiotropium + olodaterol 5/5 μg i the ad 3 subgroups for FEV 1 AUC 0 3 respose ( ml) ad TDI ( ) (Additioal file 1: Table S1). Treatmet differeces are show i Fig. 4 for FEV 1 AUC 0 3, trough FEV 1 resposes, SGRQ total score ad TDI focal score. I geeral, results i patiets weresimilartogold3,withlargercisforgold3due to the smaller umber of patiets i this group. The compariso of tiotropium + olodaterol versus placebo showed sigificat treatmet effects for all ed poits i ad 3 patiets (95 % CI did ot cross zero). The comparisos of tiotropium + olodaterol versus tiotropium showed sigificat differeces betwee treatmet for most ed poits, except for trough FEV 1, i both ad 3, ad, as discussed, SGRQ i patiets, which is most likely due to the reduced sample size as treatmet differeces are similar betwee the groups. GOLD A D subgroups Tiotropium + olodaterol was more effective at improvig FEV 1 AUC 0 3 tha tiotropium mootherapy ad placebo i GOLD A D subgroups (Fig. 5). Trough FEV 1 resposes improved sigificatly with tiotropium + olodaterol compared to placebo i GOLD A D subgroups. Improvemets with tiotropium + olodaterol were umerically compared to tiotropium mootherapy i GOLD A, B ad D groups, although these improvemets were ot sigificat, as the 95 % CI crossed zero. I geeral, lug-fuctio treatmet comparisos were similar across GOLD A D subgroups. SGRQ total score ad TDI focal score improved sigificatly, to a greater extet with tiotropium + olodaterol compared to placebo i GOLD A D groups (Fig. 5b ad c). Treatmet effects were similar betwee subgroups with overlappig 95 % CIs. Whe comparig tiotropium + olodaterol to tiotropium aloe, treatmet effects differed betwee subgroups ad improvemets i SGRQ total score were most evidet i the GOLD B subgroup. Treatmet-aive patiets Tiotropium + olodaterol was more effective tha tiotropium mootherapy ad placebo for FEV 1 AUC 0 3 ad trough FEV 1, both i patiets with ad without previous maiteace therapy, although for trough FEV 1 the 95 % CI crossed zero for the compariso with tiotropium i treatmet-aive idividuals. The effect sizes were geerally greater i those patiets who had bee receivig previous maiteace therapy (Fig. 6a). The mea improvemets i SGRQ total score ad TDI focal score were similar for patiets with ad without previous maiteace therapy ad sigificat for both treatmet comparisos (Fig. 6b ad c). ICS use at baselie Tiotropium + olodaterol was more effective at improvig lug-fuctio outcomes tha tiotropium mootherapy ad placebo, both i patiets who were receivig ICS treatmet at baselie ad those who were ot. FEV 1 AUC 0 3 ad trough FEV 1 resposes improved i both groups (Fig. 7a), with some evidece for a superior respose for patiets receivig ICS at baselie. Baselie SGRQ scores were higher for patiets receivig ICS treatmet at baselie, compared to those ot receivig baselie ICS (44.4 ad 41.5, respectively). I cotrast to lug-fuctio outcomes, the improvemet i SGRQ total scores with tiotropium + olodaterol compared to tiotropium or placebo was greater i patiets who were ot receivig ICS at baselie (Fig. 7b ad c). Respoder aalyses across subgroups Respoder aalyses for SGRQ total score demostrated that a greater proportio of patiets respoded with tiotropium + olodaterol compared to tiotropium mootherapy or placebo for all subgroups (Additioal file 1: Figure S1a) with sigificat improvemets compared to placebo i all subgroups except GOLD A. Overall, treatmet differeces for tiotropium + olodaterol compared to tiotropium mootherapy or placebo were similar betwee subgroups, with widely overlappig 95 % CIs. I the subgroup, 52.8 % of patiets i the tiotropium + olodaterol 5/5 μg arm ad 39.2 % i the

5 Table 1 Patiet demographics ad baselie characteristics by subgroups ad overall (combied OTEMTO 1 ad 2; treated set) GOLD A GOLD B GOLD C GOLD D Naive: o ICS: o Overall Patiets, Male, (%) 609 (58.4) 374 (65.6) 298 (61.3) 271 (56.1) 167 (66.8) 250 (62.5) 574 (60.9) 413 (60.9) 632 (62.4) 355 (58.4) 987 (60.9) Mea (SD) age, years 64.3 (8.7) 65.5 (7.9) 64.3 (8.1) 64.4 (9.0) 65.2 (8.6) 65.4 (7.9) 65.6 (8.2) 63.5 (8.6) 63.9 (8.4) 66.1 (8.3) 64.7 (8.4) Smokig status, (%) Ex-smoker 554 (53.2) 300 (52.6) 260 (53.5) 255 (52.8) 135 (54.0) 207 (51.8) 560 (59.4) 298 (44.0) 473 (46.7) 385 (63.3) 858 (52.9) Curret smoker 488 (46.8) 270 (47.4) 226 (46.5) 228 (47.2) 115 (46.0) 193 (48.3) 383 (40.6) 380 (56.0) 540 (53.3) 223 (36.7) 763 (47.1) Mea (SD) pre-brochodilator FEV 1, L (0.460) (0.262) (0.469) (0.445) (0.353) (0.327) (0.459) (0.521) (0.512) (0.428) (0.492) Mea (SD) post-brochodilator FEV 1, L (0.468) (0.274) (0.472) (0.455) (0.370) (0.336) (0.475) (0.532) (0.522) (0.444) (0.504) FEV 1 % predicted (7.98) (5.54) (8.08) (7.72) (9.80) (9.06) (12.86) (12.57) (12.55) (12.83) (12.81) FEV 1 /FVC ratio, % (SD) (8.21) (9.62) (8.33) (8.14) (9.83) (10.24) (10.42) (9.89) (9.96) (10.67) (10.42) Baselie pulmoary medicatio, (%) Ay 761 (73.0) 473 (83.0) 349 (71.8) 356 (73.7) 213 (85.2) 321 (80.3) 943 (100) 297 (43.8) 632 (62.4) 608 (100) 1240 (76.5) ICS 337 (32.3) 269 (47.2) 131 (27.0) 173 (35.8) 125 (50.0) 179 (44.8) 608 (64.5) 0 (0.0) 0 (0.0) 608 (100) 608 (37.5) LAMA 334 (32.1) 221 (38.8) 157 (32.3) 150 (31.1) 105 (42.0) 148 (37.0) 560 (59.4) 0 (0.0) 277 (27.3) 283 (46.5) 560 (34.5) SAMA 68 (6.5) 56 (9.8) 24 (4.9) 38 (7.9) 21 (8.4) 41 (10.3) 88 (9.3) 36 (5.3) 55 (5.4) 69 (11.3) 124 (7.6) LABA 365 (35.0) 261 (45.8) 149 (30.7) 184 (38.1) 117 (46.8) 179 (44.8) 629 (66.7) 0 (0.0) 144 (14.2) 485 (79.8) 629 (38.8) SABA 470 (45.1) 343 (60.2) 211 (43.4) 223 (46.2) 159 (63.6) 224 (56.0) 542 (57.5) 276 (40.7) 447 (44.1) 371 (61.0) 818 (50.5) GOLD A D based o modified Medical Research Coucil dyspoea scale. The iclusio criteria for this study oly icluded patiets with or 3 disease; however, 8 patiets were classed as GOLD 4 ad 1 patiet as GOLD 1 based o etrace spirometry results. As this is a small umber, these patiets were ot icluded i the /3 subgroup aalysis ad are ot icluded i the table GOLD Global iitiative for chroic Obstructive Lug Disease, ICS ihaled corticosteroids, SD stadard deviatio, FEV 1 forced expiratory volume i 1 s, FVC forced vital capacity, LAMA log-actig muscariic atagoist, SAMA short-actig muscariic atagoist, LABA log-actig β 2 -agoist, SABA short-actig β-agoist Sigh et al. Respiratory Research (2016) 17:73 Page 5 of 13

6 Sigh et al. Respiratory Research (2016) 17:73 Page 6 of Adjusted mea (SE) trough FEV1 respose, L Placebo T 5 µg T+O 5/5 µg Fig. 2 Adjusted mea trough FEV 1 resposes at 12 weeks i patiets with ad 3 disease. FEV 1 : forced expiratory volume i 1 s; GOLD: Global iitiative for chroic Obstructive Lug Disease; SE: stadard error; T: tiotropium; O: olodaterol tiotropium 5 μg arm were SGRQ respoders, compared to 33.7 % i the placebo arm. I the subgroup, 51.7 % of patiets i the tiotropium + olodaterol 5/5 μg arm ad 45.0 % i the tiotropium 5 μg arm were SGRQ respoders, compared to 28.5 % i the placebo arm. There was also a icreased proportio of TDI respoders with tiotropium + olodaterol compared to tiotropium mootherapy ad placebo i all subgroups, with similar treatmet effect overall (Additioal file 1: Figure S1b). Improvemets were sigificat compared to placebo i all subgroups ad compared to tiotropium for most of the subgroups Adjusted mea (SE) SGRQ total score Placebo T 5 µg T+O 5/5 µg Fig. 3 Adjusted mea SGRQ total score at 12 weeks i patiets with ad 3 disease. SGRQ: St George s Respiratory Questioaire; GOLD: Global iitiative for chroic Obstructive Lug Disease; SE: stadard error; T: tiotropium; O: olodaterol -5.56

7 Sigh et al. Respiratory Research (2016) 17:73 Page 7 of 13 (a) Treatmet compariso FEV 1 AUC 0 3 Trough FEV 1 252/ / / / / / / / (b) SGRQ total score Treatmet differece (adjusted mea, 95 % CI), L T+O Treatmet compariso 246/ / / / (c) Treatmet compariso TDI focal score T+O 246/ / / /132 Treatmet differece (adjusted mea, 95 % CI) Treatmet differece (adjusted mea, 95 % CI) T+O Fig. 4 (a) FEV 1 AUC 0 3 ad trough FEV 1 resposes, (b) SGRQ total score ad (c) TDI focal score, all at 12 weeks: treatmet comparisos for T + O 5/5 μg versus T 5 μg ad versus placebo i patiets with ad 3 disease. FEV 1 : forced expiratory volume i 1 s; AUC 0 3 : area uder the curve from 0 3 h; SGRQ: St George s Respiratory Questioaire; TDI: Trasitio Dyspoea Idex; T: tiotropium; O: olodaterol; GOLD: Global iitiative for chroic Obstructive Lug Disease; CI: cofidece iterval

8 Sigh et al. Respiratory Research (2016) 17:73 Page 8 of 13 (a) Treatmet compariso FEV 1 AUC 0 3 GOLD A GOLD B GOLD C GOLD D GOLD A GOLD B GOLD C GOLD D Trough FEV 1 GOLD A GOLD B GOLD C GOLD D GOLD A GOLD B GOLD C GOLD D 119/ /123 67/64 105/96 119/ /122 67/62 105/97 119/ /123 67/64 105/96 119/ /122 67/62 105/ (b) SGRQ total score T+O Treatmet differece (adjusted mea, 95 % CI), L Treatmet compariso GOLD A GOLD B 116/ /115 GOLD C 65/55 GOLD D 103/85 GOLD A 116/123 GOLD B 108/112 GOLD C 65/59 GOLD D 103/90 (c) TDI focal score T+O Treatmet differece (adjusted mea, 95 % CI) Treatmet compariso GOLD A GOLD B 116/ /116 GOLD C 65/55 GOLD D 103/84 GOLD A 116/122 GOLD B 108/113 GOLD C 65/60 GOLD D 103/ Treatmet differece (adjusted mea, 95 % CI) T+O Fig. 5 (a) FEV 1 AUC 0 3 ad trough FEV 1 resposes, (b) SGRQ total score ad (c) TDI focal score, all at 12 weeks: treatmet comparisos for T + O 5/5 μg versus T 5 μg ad versus placebo i patiets with GOLD A D disease. FEV 1 : forced expiratory volume i 1 s; AUC 0 3 : area uder the curve from 0 3 h; SGRQ: St George s Respiratory Questioaire; TDI: Trasitio Dyspoea Idex; T: tiotropium; O: olodaterol; GOLD: Global iitiative for chroic Obstructive Lug Disease; CI: cofidece iterval

9 Sigh et al. Respiratory Research (2016) 17:73 Page 9 of 13 (a) Treatmet compariso FEV 1 AUC 0 3 Naive: o Naive: o Trough FEV 1 Naive: o Naive: o 239/ / / / / / / / T+O Treatmet differece (adjusted mea, 95 % CI), L (b) SGRQ total score Treatmet compariso Naive: o Naive: o 233/ / / / T+O (c) TDI focal score Treatmet differece (adjusted mea, 95 % CI) Treatmet compariso Naive: o Naive: o 233/ / / / T+O Treatmet differece (adjusted mea, 95 % CI) Fig. 6 (a) FEV 1 AUC 0 3 ad trough FEV 1 resposes, (b) SGRQ total score ad (c) TDI focal score: treatmet comparisos at 12 weeks for T + O 5/5 μg versus T 5 μg ad versus placebo i patiets who were treatmet aive/ot treatmet aive at baselie. FEV 1 : forced expiratory volume i 1 s; AUC 0 3 : area uder the curve from 0 3 h; SGRQ: St George s Respiratory Questioaire; TDI: Trasitio Dyspoea Idex; T: tiotropium; O: olodaterol; CI: cofidece iterval

10 Sigh et al. Respiratory Research (2016) 17:73 Page 10 of 13 (a) FEV 1 AUC 0 3 ICS: o 245/ /140 Treatmet compariso ICS: o Trough FEV 1 245/ /147 ICS: o 244/ /135 ICS: o 244/ /143 (b) SGRQ T+O Treatmet differece (adjusted mea, 95 % CI) Treatmet compariso ICS: o ICS: o 240/ / / /139 (c) Treatmet compariso TDI focal score ICS: o T+O 240/ /123 ICS: o 240/ /140 Treatmet differece (adjusted mea, 95 % CI) T+O Treatmet differece (adjusted mea, 95 % CI) Fig. 7 (a) FEV 1 AUC 0 3 ad trough FEV 1 resposes, (b) SGRQ total score ad (c) TDI focal score: treatmet comparisos at 12 weeks for T + O 5/5 μg versus T 5 μg ad versus placebo i patiets who were receivig/ ot receivig ICS treatmet at baselie. FEV 1 : forced expiratory volume i 1 s; AUC 0 3 : area uder the curve from 0 3 h; SGRQ: St George s Respiratory Questioaire; TDI: Trasitio Dyspoea Idex; T: tiotropium; O: olodaterol; ICS: ihaled corticosteroids; CI: cofidece iterval

11 Sigh et al. Respiratory Research (2016) 17:73 Page 11 of 13 Discussio The OTEMTO studies demostrated that tiotropium + olodaterol improved lug fuctio ad quality of life i patiets with moderate to severe COPD. Subgroup aalyses cofirm that tiotropium + olodaterol is equally effective i patiets with moderate COPD (), as for those with severe disease (). Usig the GOLD A D categorisatio, tiotropium + olodaterol showed a similar effect o lug fuctio i all the subgroups but the beefit of this dual brochodilator combiatio versus tiotropium mootherapy o patietreported outcomes was most apparet i GOLD B patiets. Tiotropium + olodaterol was also superior to tiotropium mootherapy irrespective of previous treatmet history, eve i those patiets aive to all maiteace therapy. The respoder aalyses are a alterative way of uderstadig the treatmet effects o patiet-reported outcomes. Importatly, there was a greater proportio of SGRQ ad TDI respoders with tiotropium + olodaterol compared to tiotropium i patiets, demostratig the potetial beefits of tiotropium + olodaterol i terms of quality of life for patiets with moderate disease. Post hoc aalyses of the TONADO studies showed that tiotropium + olodaterol was superior to tiotropium ad olodaterol mootherapies for lug-fuctio chages i patiet subgroups classified by lug-fuctio impairmet severity, age ad previous treatmet history [19]. Our aalyses geerally agree with these previous fidigs o lug fuctio ad further exted these observatios by ivestigatig resposes i patiets with GOLD A D disease, as well as ivestigatig patiet-reported outcomes. The aalysis of patiets with GOLD A D disease showed that the effects of tiotropium + olodaterol o lug fuctio versus tiotropium mootherapy or placebo were similar i all subgroups. However, for SGRQ, the beefit of tiotropium + olodaterol was most apparet i GOLD B patiets. There has bee some debate about which patiets with COPD beefit most from dual brochodilator treatmet compared to log-actig brochodilator mootherapy. The curret fidigs i GOLD B patiets suggest that the symptomatic beefit of tiotropium + olodaterol is greater i patiets with higher baselie symptoms ad FEV 1 >50 % predicted ad this may idicate that early combied treatmet would be beeficial for these patiets. The treatmet differece was less proouced i GOLD D patiets compared to GOLD B patiets, suggestig that i highly symptomatic patiets with COPD (i.e. GOLD B ad D) the greatest beefit of LAMA + LABA compared to log-actig brochodilator mootherapy o patietreported outcomes is i patiets with less severe airflow obstructio, although all groups showed beefit from LAMA + LABA therapy. A ote of cautio for this iterpretatio of the GOLD A D aalysis is that the patiets were split ito four subgroups, thereby producig thesmallestsamplesizeofalltheaalysespreseted here, ad this reduced sample size may ifluece these results. There was a tred towards greater lug-fuctio improvemets with tiotropium + olodaterol i patiets who had received previous maiteace therapy. However, this patter did ot traslate to a greater beefit o patiet-reported outcomes. The mea treatmet effects were similar i both groups of patiets ad the wide 95 % CI for the treatmet effect i patiets receivig previous maiteace treatmet suggests a large variatio betwee idividuals i this group, ad results may have bee iflueced by selectio bias. Overall, we coclude that treatmet with tiotropium + olodaterol showed evidece of similar efficacy, irrespective of previous maiteace treatmet. I this study, there was a large proportio of patiets receivig ICS treatmet at baselie, the majority of whom were classed as havig severe or very severe ( or GOLD C/D) disease. This is i accordace with curret GOLD guidelies, which recommed ICS treatmet for patiets with severe/very severe COPD ad frequet exacerbatios who are ot adequately cotrolled with log-actig brochodilators [1]. Cliical trials of LAMA + LABA combiatios usually allow patiets receivig ICS treatmet to cotiue durig the study. This is mostly for ethical reasos, as steppig patiets dow from both log-actig brochodilator treatmet ad ICS i the placebo arm is potetially usafe. However, the use of LAMA + LABA combiatio ihalers i real life is likely to be mostly without cocomitat ICS treatmet. Although this sub-aalysis of OTEMTO caot exclude a effect of ICS treatmet o the cliical respose to tiotropium + olodaterol, it would appear that ay effect, if preset, is small. Further studies are required to assess whether patiets with GOLD D disease should be treated with LAMA + LABA or LAMA + LABA + ICS. The mai limitatios of these aalyses are that they are post hoc ad ot powered for statistical comparisos betwee subgroups. However, as the aalyses were performed to cofirm that the positive results of the OTEMTO study hold true for patiets of all disease severities icluded, ad for patiets irrespective of prior medicatio use, this is ot a major cocer. A patter of results for the lug-fuctio chages oted i this subgroup aalysis is that ofte the 95 % CI for tiotropium + olodaterol versus tiotropium crossed zero for trough FEV 1 but ot for FEV 1 AUC 0 3. This, agai, is likely to be related to sample size for these subgroups ad the greater effect size for AUC 0 3.

12 Sigh et al. Respiratory Research (2016) 17:73 Page 12 of 13 Oe reaso why it is of iterest to examie the beefits of tiotropium + olodaterol i patiets by disease severity, ad i patiets who are treatmet aive, is that the fastest declie i lug fuctio i COPD is see i the iitial stages of the disease [20]. Thus, selectig the most appropriate treatmet for iitial therapy may be importat. Eve i mild to moderate COPD, patiets start to limit exercise ad activities, which are further limited as lug fuctio declies, leadig to a sedetary lifestyle [21]. It has bee suggested that iterveig early i COPD may beefit patiets, as they are able to maitai levels of activity ad health [20], ad treatmet may improve healthrelated quality of life ad potetially slow disease progressio [22]. Furthermore, a subgroup aalysis of the UPLIFT tiotropium study showed that i patiets with (moderate) COPD, early itervetio with tiotropium appeared to slow the course of FEV 1 declie [23]. Improvemets i lug fuctio are associated with quality of life ad reduced symptoms [24]. By targetig earlier disease, it is hoped that treatmet may maitai the patiet s fuctioality ad postpoe disease progressio for loger. Coclusios Overall, the added beefits of tiotropium + olodaterol compared to tiotropium mootherapy i patiets with moderate COPD ad treatmet-aive patiets suggest that tiotropium + olodaterol should be cosidered as a optio for patiets at the poit where there is a eed to iitiate maiteace therapy, as well as i patiets with more severe disease. Additioal file Additioal file 1: Methodology; Table S1. Trough FEV 1 ad FEV 1 AUC 0 3 resposes, TDI focal score ad SGRQ total score at 12 weeks i ad subgroups (full aalysis set, combied studies); Figure S1. (a) Respoder aalysis of SGRQ total score ad (b) TDI focal score, all at 12 weeks: treatmet comparisos for T + O 5/5 μg versus T 5 μg ad versus placebo i patiets with ad 3 disease, GOLD A D disease, patiets who were treatmet aive/ot treatmet aive at baselie ad for patiets who were receivig/ot receivig ICS treatmet at baselie. (DOCX 333 kb) Abbreviatios AUC 0 3, area uder the curve from 0 to 3 h; CI, cofidece iterval; COPD, chroic obstructive pulmoary disease; FEV 1, forced expiratory volume i 1 s; GOLD, Global iitiative for chroic Obstructive Lug Disease; ICS, ihaled corticosteroids; LABA, log-actig β 2 -agoist; LAMA, log-actig muscariic atagoist; SGRQ, St George s Respiratory Questioaire; TDI, Trasitio Dyspoea Idex Ackowledgemets The authors received o compesatio related to the developmet of the mauscript. Medical writig assistace was provided by Claire Scofield, MRes, ad Laura George, PhD, of Complete HealthVizio. Fudig This work was supported by Boehriger Igelheim Pharma GmbH & Co. KG. Medical writig assistace was cotracted ad compesated by Boehriger Igelheim Pharma GmbH & Co. KG. Authors cotributios All authors have cotributed to the coceptio/desig of the study, data acquisitio or aalysis ad iterpretatio of the data. All authors meet criteria for authorship as recommeded by the Iteratioal Committee of Medical Joural Editors. They take full resposibility for the scope, directio, cotet of, ad editorial decisios relatig to, the mauscript, were ivolved at all stages of developmet ad have approved the submitted mauscript. DS was the coordiatig ivestigator of the study ad participated i the desig, implemetatio ad iterpretatio of the study. MG, OS ad GTF were study ivestigators ad participated i the coordiatio ad iterpretatio of the study. LG was the medical lead i the study ad participated i the desig, coordiatio ad iterpretatio of the study. FV performed the statistical aalyses ad was ivolved i the iterpretatio of the study. All authors read ad approved the fial mauscript. Competig iterests DS reports cosultacy fees from Boehriger Igelheim durig the coduct of the study, grats ad persoal fees from Almirall, AstraZeeca, Boehriger Igelheim, Chiesi, GlaxoSmithKlie, Glemark, Johso ad Johso, Merck, NAPP, Novartis, Pfizer, Takeda, Teva, Therevace ad Veroa, ad persoal fees from Geetech ad SkyePharma outside the submitted work. MG reports grats, cosultacy fees ad travel support from Boehriger Igelheim durig the coduct of the study ad grats, cosultacy fees ad paymets for lectures/speaker Bureaus from GlaxoSmithKlie, Novartis, AstraZeeca, Boehriger Igelheim, Pfizer, ELPEN ad Pharmathe outside the submitted work. OS reports grats, persoal fees ad o-fiacial support from Boehriger Igelheim durig the coduct of the study ad grats, persoal fees ad o-fiacial support from Boehriger Igelheim, Pfizer, Almirall, AstraZeeca, Chiesi, GlaxoSmithKlie, Novartis, Takeda, Amge, Cephalo, Geetech/Roche, Teva ad MSD outside the submitted work. GTF reports grats, persoal fees ad o-fiacial support from Boehriger Igelheim durig the coduct of the study ad grats, persoal fees ad o-fiacial support from Boehriger Igelheim, grats ad persoal fees from Novartis, AstraZeeca, Pearl Therapeutics ad Suovia, grats from Forest ad persoal fees from GlaxoSmithKlie outside the submitted work. LG ad FV are employees of Boehriger Igelheim. LB reports o coflicts of iterest. Author details 1 Cetre for Respiratory Medicie ad Allergy, The Medicies Evaluatio Uit, Uiversity Hospital of South Machester Foudatio Trust, Uiversity of Machester, Machester, Southmoor Road, Machester M23 9QZ, UK. 2 Athes Chest Hospital, Athes, Greece. 3 Luge- ud Brochialheilkude, Koblez, Germay. 4 Departmet of Respiratory Medicie ad Allergology, Lud Uiversity, Lud, Swede. 5 Boehriger Igelheim Pharma GmbH & Co. KG, Igelheim, Germay. 6 Pulmoary Research Istitute of Southeast Michiga, Farmigto Hills, MI, USA. Received: 9 April 2016 Accepted: 3 Jue 2016 Refereces 1. Global Iitiative for Chroic Obstructive Lug Disease. Global strategy for the diagosis, maagemet, ad prevetio of chroic obstructive pulmoary disease. Updated Accessed 6 Ju Natioal Istitute for Health ad Care Excellece. Chroic obstructive pulmoary disease i over 16 s: diagosis ad maagemet. Cliical guidelie. NICE guidelies [CG101]. resources/chroic-obstructive-pulmoary-disease-i-over-16s-diagosis-admaagemet Accessed 6 Ju Casaburi R, Mahler DA, Joes PW, Waer A, Sa Pedro G, ZuWallack RL, et al. A log-term evaluatio of oce-daily ihaled tiotropium i chroic obstructive pulmoary disease. Eur Respir J. 2002;19: O Doell DE, Flüge T, Gerke F, Hamilto A, Webb K, Aguilaiu B, et al. Effects of tiotropium o lug hyperiflatio, dyspoea ad exercise tolerace i COPD. Eur Respir J. 2004;23:

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